Phase II trial of pembrolizumab in patients with brain metastases.
Authors: Priscilla Kaliopi Brastianos, Albert Eusik Kim, Anita Giobbie-Hurder, Eudocia Quant Lee, Nancy U. Lin, Beth Overmoyer, Patrick Y. Wen, Lakshmi Nayak, Justine Vanessa Cohen, Jorg Dietrich, Rebecca Suk Heist, Ian E. Krop, Donald P. Lawrence, Erica L. Mayer, Eric P. Winer, Helen Alice Shih, Kevin S. Oh, Daniel P. Cahill, Elizabeth R Gerstner, Ryan J. Sullivan
Journal: Journal of Clinical Oncology (2023)

2006 Background: Brain metastases are an increasing challenge in oncology due to increasing incidence and limited treatments. Recent studies suggest that brain metastases harbor a tumor microenvironment characterized by immunosuppressive phenotypes, which contribute to treatment resistance. Therefore, a logical therapeutic strategy for brain metastases is to evaluate immune-based strategies that augment T cell cytotoxicity. Methods: This study was designed as an open-label, single-stage, single-arm phase 2 clinical trial evaluating the intracranial efficacy of pembrolizumab, a PD-1 inhibitor, in patients with brain metastases of diverse histologies. The target accrual was 58 patients to achieve at least 52 evaluable patients (i.e., received at least one dose of pembrolizumab). The primary endpoint was intracranial benefit, defined as a best response of complete response, partial response, or stable disease by RANO criteria during treatment. The study design compared a null intracranial benefit rate of 10% against an alternative of 24%. If at least 8 patients among the total of 52 had intracranial benefit, the primary efficacy endpoint would be met and pembrolizumab would be considered worthy of further study in this patient population. This design has a type-I error of 10% and power of 89% (target type-II error of 15%). Results: In the 57 evaluable patients, median age was 53 (range 28-80) and 81% were female. Tumor histologies included breast (n = 35), non-small cell lung cancer (n = 7), melanoma (n = 2), small-cell lung cancer (n = 2), sarcoma (n = 2), ovarian (n = 1), pituitary carcinoma (n = 1), pituitary neuroendocrine tumor (n = 1), esophageal adenocarcinoma (n = 1), prostate (n = 1), renal cell carcinoma (n = 1), neuroendocrine carcinoma (n = 1), unknown primary (n = 1) and sinonasal adenocystic carcinoma (n = 1). For the patients with breast cancer, 16 patients had HER-2 positive disease, 17 patients had hormone receptor-positive disease, and 11 patients had the triple-negative subtype. The study met its primary endpoint and achieved an intracranial benefit rate of 42.1% (90% confidence interval [CI]: 31-54%). In addition, seven patients, who had either breast cancer, melanoma or sarcoma, had durable intracranial anti-tumor activity ( &gt; 2 years). The extracranial benefit rate in patients with evaluable extracranial disease based on RECIST 1.1 criteria was 45% (18/40; 90% CI: 31-59%). Median overall survival was 8.0 months (90% CI: 5.5-8.7 months). Grade 4 toxicities at least possibly related to treatment were observed in 2 patients: cerebral edema (n = 2). Thirteen patients discontinued treatment for adverse events. Conclusions: Our study of pembrolizumab met overall primary endpoint for intracranial benefit in patients with brain metastases. These results suggest that PD-1 blockade may serve as the backbone of therapeutic strategies for a select group of patients with brain metastases and warrants further evaluation. Clinical trial information: NCT02886585 .